Alkylated (hetero) cyclic compounds

ABSTRACT

The invention relates to a compounds selected from these of formula (I): ##STR1## in which: R 1 , R 2 , R 3  and A are as defined in the description, and a medicinal product containing the same useful for treating a melatoninergic disorder.

The present application is a division of our prior-filed copendingapplication Ser. No. 08/584,465, filed Jan. 10, 1996, now pending.

FIELD OF THE INVENTION

The invention relates to novel alkylated (hetero)cyclic compounds, to aprocess for their preparation and to the pharmaceutical compositionswhich contain them.

The invention describes novel alkylated (hetero)cyclic compounds whichprove to be powerful ligands for melatoninergic receptors.

In the last ten years, many studies have demonstrated the fundamentalrole of melatonin (5-methoxy-N-acetyltryptamine) in controllingcircadian rhythm and endocrine functions, and the melatonin receptorshave been characterized and localized.

Besides their beneficial action on disorders of circadian rhythm (J.Neurosurg., 1985, 63, pp 321-341) and on sleeping disorders(Psychopharmacology, 1990, 100, pp 222-226), ligands for themelatoninergic system possess advantageous pharmacological propertieswith regard to the central nervous system, in particular anxiolytic andantipsychotic properties (Neuropharmacology of Pineal Secretions, 1990,8 (3-4), pp 264-272) and analgesic properties (Pharmacopsychiat., 1987,20, pp 222-223) as well as for the treatment of Parkinson's disease (J.Neurosurg., 1985, 63, pp 321-341) and Alzheimer's disease (BrainResearch, 1990, 528, pp 170-174). Similarly, these compounds have shownan activity on certain cancers (Melatonin--clinical Perspectives, OxfordUniversity Press, 1988, page 164-165), on ovulation (Science 1987, 227,pp 714-720), and on diabetes (Clinical endocrinology, 1986, 24, pp359-364).

Compounds whch make it possible to act on the melatoninergic system arethus excellent medicinal products, for clinicians, for the treatment ofthe pathologies mentioned above.

The invention relates to the compounds of formula (I): ##STR2## inwhich: R₁ represents a radical chosen from alkyl, substituted alkyl,cycloalkyl, substituted cycloalkyl, cycloalkylalkyl and substitutedcycloalkylalkyl,

A forms, with the benzene ring to which it is attached, a cyclic groupchosen from tetrahydronaphthalene, dihydronaphthalene, naphthalene,benzothiophene, 2,3-dihydrobenzothiophene, indoline, substitutedindoline, indole and substituted indole,

R₂ represents a hydrogen or an alkyl,

R₃ represents:

a group R₃₁ : ##STR3## with X representing a sulfur or an oxygen and R₄representing a hydrogen or a radical R₄₁ chosen from alkyl, substitutedalkyl, alkenyl, alkynyl, cycloalkyl, substituted cycloalkyl,cycloalkylalkyl and substituted cycloalkylalkyl,

or a group of formula (R₃₂): ##STR4## with X' representing a sulfur oran oxygen and R₅ representing a hydrogen or a radical chosen from alkyl,substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkylalkyland substituted cycloalkylalkyl,

it being understood that in the description of formula (I), and exceptwhere otherwise mentioned:

the terms "alkyl" and "alkoxy" denote linear or branched groupscontaining from 1 to 6 carbon atoms,

the terms "alkenyl" and "alkynyl" denote linear or branched groupscontaining from 2 to 6 atoms,

the term "cycloalkyl" denotes a group of 3 to 8 carbon atoms,

the term "substituted" associated with the alkyl radical means that thisradical is substituted with one or more substituents chosen fromhalogen, "alkyl", hydroxyl and alkoxy,

the term "substituted" associated with the "cycloalkyl" and"cycloalkylalkyl" radicals means that this radical is substituted withone or more radicals or groups chosen from halogen, alkyl and oxo,

the term "substituted" associated with the terms "indole" and "indoline"means that these groups are substituted on the nitrogen in the1-position with a radical chosen from --Ra, --CO--Ra and --CO--O--Ra inwhich Ra represents an alkyl, phenyl or phenylalkyl radical,

and the enantiomers and diastereoisomers thereof.

The invention relates more particularly to the compounds of formula (I)in which, taken separately or together,

R₁ represents an alkyl,

R₁ represents a (C_(2-C) ₆)alkyl,

R₁ represents an ethyl,

R₁ represents a propyl,

R₁ represents a butyl,

A forms, with the benzene ring to which it is attached, atetrahydronaphthalene,

A forms, with the benzene ring to which it is attached, a naphthalene,

A forms, with the benzene ring to which it is attached, adihydronaphthalene,

A forms, with the benzene ring to which it is attached, abenzothiophene,

A forms, with the benzene ring to which it is attached, an indole,

A forms, with the benzene ring to which it is attached, a substitutedindole,

R₂ represents a hydrogen,

R₂ represents an alkyl,

R₃ represents a group R₃₁ as defined in formula (I),

R₃ represents a group R₃₂ as defined in formula (I),

R₄ represents a hydrogen atom,

R₄ represents an alkyl,

R₄ represents a cycloalkyl,

R₄ represents an alkenyl,

R₅ represents a hydrogen,

R₅ represents an alkyl,

R₅ represents a cycloalkyl,

X represents an oxygen,

X represents a sulfur,

X' represents an oxygen,

or X' represents a sulfur.

For example, the invention relates to the specific compounds of formula(I) corresponding to the respective formulae (1) to (5): ##STR5##

The invention relates particularly to the compounds of formula (I), forexample the specific compounds of formulae (1) to (5), as defined abovein which R₁ is:

in position a of the benzene ring,

in position b of the benzene ring,

in position c of the benzene ring,

or in position d of the benzene ring.

For example, te invention relates to the compounds of formula (I) inwhich R₁ is in position b of the benzo ring.

The invention specifically relates to the following compounds:

N- 2-(5-ethylbenzothiophen-3-yl)ethyl!acetamide,

N- 2-(5-ethylbenzothiophen-3-yl)ethyl!cyclobutanecarboxamide,

N- 2-(7-ethyl-1,2,3,4-tetrahydronaphth-1-yl)ethyl!acetamide,

N- 2-(7-ethyl-1,2,3,4-tetrahydronaphth-1-yl)ethyl!butyramide,

N-2-(7-ethyl-1,2,3,4-tetrahydronaphth-1-yl)ethyl!cyclopropanecarboxamide,

N- 2-(7-ethyl-1,2,3,4-tetrahydronaphth-1-yl)ethyl!pentanamide,

and N- 2-(7-ethyl-1,2,3,4-tetrahydronaphth-1-yl)ethyl!trifluoroacetamide.

The alkyl radicals present in formula (I) may specifically be chosenfrom methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,tert-butyl, pentyl and hexyl.

The alkoxy radicals present in formula (I) may be chosen from methoxy,ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy,tert-butoxy, pentyloxy and hexyloxy.

The halogens present in formula (I) may be chosen from bromine,chlorine, fluorine and iodine.

The cycloalkyls present in formula (I) may be chosen from cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

The invention also relates to the process for the preparation of thecompounds of formula (I), wherein:

a compound of formula (Il): ##STR6## in which R₁ and A are as defined informula (I), is reacted either with formic acid or with a compound offormula (IIIa) or (IIIb): ##STR7## in which R₄₁ is as defined in formula(I) and Hal represents a halogen, in order to obtain the compounds offormula (I/a): ##STR8## in which R₁, R₂, R₄ and A are as defined above,which compounds of formula (I/a) are treated with Lawesson's reagent inorder to obtain the compounds of formula (I/a'): ##STR9## in which R₁,R₂, R₄ and A are as defined above, or with a compound of formula (IV):

    X'═C═N--R.sub.5                                    (IV)

in which X' and R₅ are as defined in formula (I)

in order to obtain the compounds of formula (I/b): ##STR10## in whichR₁, R₂, R₅, A and X' are as defined above, the compounds of formulae(I/a), (I/a') and (I/b) forming the set of compounds of formula (I),which compounds of formula (I) are, where appropriate, separated intothe various enantiomers or diastereoisomers thereof.

For example, the invention covers the process for the preparation of thecompounds of formula (I/c): ##STR11## in which R₁, R₂ and R₃ are asdefined in formula (I), wherein:

a compound of formula (II/a): ##STR12## in which R₁ and R₂ are definedas above, is reacted either with a compound of formula (IIIa) or (IIIb)as defined above,

in order to obtain the compounds of formula (I/d): ##STR13## in whichR₁, R₂ and R₄ are as defined above, which compounds are then treatedwith Lawesson's reagent in order to obtain the compounds of formula(I/d'): ##STR14## in which R₁, R₂ and R₄ are as defined above, or with acompound of formula (IV) as defined above,

in order to obtain the compounds of formula (I/e): ##STR15## in whichR₁, R₂, R₅ and X' are as defined above, the compounds of formula (I/d),(I/d') and (I/e) forming the set of compounds of formula (I/c), it beingpossible for the compounds of formula (I/c) to be separated into thevarious enantiomers or diastereoisomers thereof.

For example, the invention also covers the process for the preparationof the compounds of formula (I/f): ##STR16## in which R₁, R₂ and R₃ areas defined in formula (I), wherein:

a compound of formula (II/b): ##STR17## in which R₁ and R₂ are asdefined above, is reacted either with a compound of formula (IIIa) or(IIIb) as defined above,

in order to obtain the compounds of formula (I/g): ##STR18## in whichR₁, R₂ and R₄ are as defined above, which compounds are then treatedwith Lawesson's reagent in order to obtain the compounds of formula(I/g'): ##STR19## in which R₁, R₂ and R₄ are as defined above, or with acompound of formula (IV) as defined above, in order to obtain thecompounds of formula (I/h): ##STR20## in which R₁, R₂, R₅ and X' are asdefined above, the compounds of formula (I/g), (I/g') and (I/h) formingthe set of compounds of formula (I/f), it being possible for thecompounds of formula (I/f) to be separated into the various enantiomersor diastereoisomers thereof.

The starting materials used in the processes described above are eithercommercial or are readily accessible to those skilled in the art bymeans of the literature and the preparation examples given below.

For example, it is possible to prepare the compounds of formula (II/a):##STR21## in which R₁ and R₂ are as defined in formula (I), by reactionof a compound of formula (V): ##STR22## in which R₁ is as defined above,with succinic anhydride in order to obtain a compound of formula (VI):##STR23## in which R₁ is as defined above, which compound is reduced inorder to obtain a compound of formula (VII): ##STR24## in which R₁ is asdefined above, which compound is then cyclized in order to obtain acompound of formula (VIII): ##STR25## in which R₁ is as defined above,which compound is reacted with diethyl cyanomethyl phosphonate in orderto obtain the compound of formula (IX): ##STR26## in which R₁ is asdefined above, which compound is then hydrogenated in order to obtainthe compound of formula (II/c): ##STR27## in which R₁ is as definedabove, which compound of formula (II/c) is optionally alkylated on theamine function in order to obtain a compound of formula (II/d):##STR28## in which R₁ is as defined above and R'₂ represents a (C₁-C₆)alkyl radical, the compounds of formulae (II/c) and (II/d) formingthe set of compounds of formula (II/a), it being possible for thecompounds of formula (II/a) to be separated into the enantiomers ordiastereoisomers thereof and salified with a pharmaceutically acceptableacid.

The aromatization of the compounds of tetrahydronaphthalene structure asdescribed above makes it possible to obtain compounds which are usefulfor the preparation of the compounds of formula (I) in which A forms,with the benzene ring to which it is attached, a naphthalene ring.

Another. preparation example for the compounds of formula (II) consistsin the process for the preparation of the compounds of formula (II/e):##STR29## in which R₁ and R₂ are as defined in formula (I) and Grepresents a sulfur or an -NH group,

wherein a compound of formula (X): ##STR30## in which R₁ and G are asdefined above, is reacted with ethyl 4-chloroacetoacetate in order toobtain the compound of formula (XI): ##STR31## in which R₁ and G are asdefined above, which compound is cyclized in order to obtain a compoundof formula (XII), ##STR32## in which R₁ and G are as defined above,which compound is hydrolyzed in order to obtain the compound of formula(XIII): ##STR33## in which R₁ and G are as defined above, which compoundis amidated in order to obtain a compound of formula (XIV): ##STR34## inwhich R₁ and G are as defined above, which compound is dehydrated to thenitrile and then reduced in order to obtain a compound of formula(II/f): ##STR35## in which R₁ and G are as defined above, which compoundof formula (II/e) is optionally alkylated on the amine function in orderto obtain a compound of formula (II/g): ##STR36## in which R₁ and G areas defined above and R'₂ represents a (C₁ -C₆)alkyl radical, thecompounds of formulae (II/f) and (II/g) forming the set of compounds offormula (II/d), it being possible for the compounds of formula (II/e) tobe salified with a pharmaceutically acceptable acid.

More particularly, the preparation of the compounds of formula (II/d) isaccessible when G represents a sulfur.

Among the pharmaceutically acceptable acids which may be used to form anaddition salt with the compounds of formula (II), there may bementioned, by way of non-limiting examples, hydrochloric acid, sulfuricacid, phosphoric acid, tartaric acid, malic acid, maleic acid, fumaricacid, oxalic acid, methanesulfonic acid, ethanesulfonic acid, camphoricacid and citric acid.

The compounds of formula (I) possess pharmacological properties whichare very advantageous for clinicians.

The compounds of the invention and the pharmaceutical compositionscontaining them prove to be useful for the treatment of disorders of themelatoninergic system.

Pharmacological study of the compounds of the invention has indeed shownthat they were not toxic, were endowed with a very selective affinityfor the melatonin receptors and had considerable activities on thecentral nervous system and, in particular, therapeutic properties withregard to sleeping disorders, anxiolytic, antipsychotic and analgesicproperties were found, as well as therapeutic properties with regard tomicrocirculation, which make it possible to establish that the productsof the invention are useful in the treatment of stress, sleepingdisorders, anxiety, seasonal depressions, cardiovascular pathologies,insomnia and fatigue due to changes in time zone, schizophrenia, panicattacks, melancholia, appetite disorders, obesity, insomnia, psychoticdisorders, epilepsy, Parkinson's disease, senile dementia, variousdisorders associated with normal or pathological ageing, migraine,memory loss, Alzheimer's disease, and disorders of cerebral circulation.In another field of activity, it is seen that the products of theinvention possess immunomodulatory and ovulation-inhibitory propertiesand that they can be used in anticancer treatment.

The compounds will preferably be used in the treatment of seasonaldepressions, sleeping disorders, cardiovascular pathologies, insomniaand fatigue due to changes in time zone, appetite disorders and obesity.

For example, the compounds will be used in the treatment of seasonaldepressions and sleeping disorders.

Another subject of the present invention is the pharmaceuticalcompositions containing the products of formula (I) in combination withone or more pharmaceutically acceptable excipients.

Among the pharmaceutical compositions according to the invention whichmay be mentioned more particularly are those which are suitable fororal, parenteral, nasal per- or transcutaneous, rectal, perlingual,ocular or respiratory administration, and in particular simple or coatedtablets, sublingual tablets, sachets, packets, gelatin capsules,glossettes, lozenges, suppositories, creams, salves, dermal gels, anddrinkable or injectable ampules.

The dosage varies depending on the sex, age and weight of the patient,the route of administration, the nature of the therapeutic indication,or on treatments which may be associated, and is graded between 0.1 mgand 1 g per 24 hours taken in 1 or 2 doses, more particularly between 1and 100 mg, for example between 1 and 10 mg.

The examples which follow illustrate the invention, but do not limit itin any way.

PREPARATION 1: 2-(7-ETHYL-1 ,2,34-TETRAHYDRONAPHTH-1-YL)ETHYLAMINE

STAGE A: 4-OXO-4-(4-ETHYLPHENYL)BUTYRIC ACID

Reactants:

    ______________________________________                                        Ethylbenzene:       0.05 mol (5 cm.sup.3)                                     Aluminum chloride:  0.02 mol (2.6 g)                                          Succinic anhydride: 0.01 mol (1 g)                                            ______________________________________                                    

Procedure:

5 cm³ of ethylbenzene and 2.6 g of aluminum chloride are mixed togetherwith magnetic stirring in a 50 cm³ flask. The solution is cooled in anice bath and 1 g of succinic anhydride is then added. The mixture isstirred for 1 h 30 at a temperature of 0° C. and then for 3 h at roomtemperature.

The reaction mixture is poured into ice.

This mixture is acidified by addition of 1N hydrochloric acid (pH 3-4).It is extracted with 3 volumes of ether. The organic phases are washed 3times with 10% potassium carbonate solution. The aqueous phases arecombined and acidified by addition of concentrated hydrochloric acid.

The precipitate obtained is drained and then recrystallized.

Characteristics:

206.23 g/mol for C₁₂ H₁₄ O₃

White powder

Melting point: 106°-108° C.

Rf=0.36; eluent: acetone/toluene/cyclohexane (2/2/1)

Recrystallization solvent: cyclohexane

Yield: 57% ##STR37## Infrared spectroscopy analysis:

    ______________________________________                                        2960-2920 cm.sup.-1 :                                                                             υ CH alkyl                                        1710 cm.sup.-1 :    υ CO acid                                         1670 cm.sup.-1 :    υ CO ketone                                       1600 cm.sup.-1 :    υ C═C aromatic                                ______________________________________                                    

Proton NMR spectroscopic analysis (80 MHz, DMSO-d₆, δ):

    ______________________________________                                         1.2 ppm (triplet, 3H):                                                                         CH.sub.3 (a) J.sub.a-b = 6.60 Hz                             2.6 ppm (multiplet, 4H):                                                                       CH.sub.2 (b) and CH.sub.2 (d)                                                              Jb - a = Jd- c =                                                              6.60 Hz                                         3.2 ppm (triplet, 2H):                                                                         CH.sub.2 (c) Jc - d = 6.60 Hz                                7.4 ppm (doublet, 2H):                                                                         H.sub.3 and H.sub.5                                                                        J.sub.ortho = 8.80 Hz                           7.9 ppm (doublet, 2H):                                                                         H.sub.2 and H.sub.6                                                                        J.sub.ortho = 8.80 Hz                          12.1 ppm (multiplet, 1H):                                                                       COOH                                                        ______________________________________                                    

3.2 ppm (triplet, 2H):CH₂ (c) Jc-d =6.60 Hz

7.4 ppm (doublet, 2H):H₃ and H₅ J_(ortho) =8.80 Hz

7.9 ppm (doublet, 2H):H₂ and H₆ J_(ortho) =8.80 Hz

12.1 ppm (multiplet, 1H):COOH

Mass spectrometric analysis:

    ______________________________________                                        m/e            206:        M.sup.+                                            m/e            207:        (M + 1).sup.+                                      ______________________________________                                    

STAGE B: 4-(4-ETHYLPHENYL)BUTYRIC ACID ##STR38## Reactants:

4-Oxo4-(4-ethylphenyl)butyric acid (Stage A):0.012 mol (2.5 g)

Triethylsilane:0.028 mol (3.2 g)

Trifluoroacetic acid:0.12 mol (19 cm³)

Procedure:

2.5 g of 4-oxo4-(4-ethylphenyl)butyric acid are dissolved in 19 cm³ oftrifluoroacetic acid with magnetic stirring in a 100 cm³ flask. 3.2 g oftriethylsilane are added dropwise.

The mixture is stirred for 86 hours at room temperature.

The reaction mixture is poured into ice.

It is extracted with 3 volumes of ether. The organic phases are washed 3times with 10% potassium carbonate solution. The aqueous phases arecombined and then acidified by addition of concentrated hydrochloricacid, to pH 3-4.

The precipitate obtained is drained and then recrystallized.

Characteristics:

192.25 g/mol for C₁₂ H₁₆ O

White powder

Melting point: 71°-73° C.

Rf=0.67, eluent: acetone/toluene/cyclohexane (2/2/1)

Recrystallization solvent: water

Yield: 65%

Infrared spectroscopic analysis:

    ______________________________________                                        3280-2780 cm.sup.-1 :                                                                             υ OH acid                                         2940-2850 cm.sup.-1 :                                                                             υ CH alkyl                                        1680 cm.sup.-1 :    υ CO acid                                         1510 cm.sup.-1 :    υ C═C aromatic                                ______________________________________                                    

Proton NMR spectroscopic analysis (300 MHz, DMSO-d₆, δ):

    ______________________________________                                        1.14 ppm (triplet, 3H):                                                                          CH.sub.3 (a)  J.sub.a-b = 7.63 Hz                          1.76 ppm (multiplet, 2H):                                                                        CH.sub.2 (d)                                               2.20 ppm (triplet, 2H):                                                                          CH.sub.2 (e)  J.sub.d-e = 7.65 Hz                          2.55 ppm (multiplet, 4H):                                                                        CH.sub.2 (c) and CH.sub.2 (b)                              7.11 ppm (multiplet, 6H):                                                                        aromatic H                                                 Acidic OH not observed                                                        ______________________________________                                    

Mass spectrometric analysis:

    ______________________________________                                        m/e            192:        M.sup.+                                            m/e            193:        (M + 1).sup.+                                      ______________________________________                                    

STAGE C: 7-ETHYL-1 -TETRALONE ##STR39## Reactants:4-(4-Ethylphenyl)butyric acid (Stage B):0.013 mol (2.5 g) Polyphosphoricacid:25g

Procedure:

25 g of polyphosphoric acid are poured into a 100 cm³ ground-neckedround-bottomed flask.

2.5 g of 4-(4-ethylphenyl)butyric acid are added. The mixture is stirredfor 6 h at a temperature of 45° C. The reaction mixture is poured intoice. It is extracted with 3 volumes of ether. The organic phases arewashed 3 times with 10% potassium carbonate solution, dried overmagnesium sulfate and then evaporated to dryness.

The oil obtained is purified by column chromatography.

Characteristics:

174.23 g/mol for C₁₂ H₁₄ O₂

Colorless oil

Rf=0.35; eluent: toluene/cyclohexane (1/2)

Yield: 55%

Infrared spectroscopic analysis:

    ______________________________________                                        3010 cm.sup.-1 :    ν CH aromatic                                          2980-2860 cm.sup.-1 :                                                                             ν CH alkyl                                             1680 cm.sup.-1 :    ν CO ketone                                            1605 cm.sup.-1 ::   ν C═C aromatic                                     ______________________________________                                    

Proton NMR spectroscopic analysis (300 MHz, DMSO-d₆, δ):

    ______________________________________                                        1.13 ppm (triplet, 3H):                                                                            CH.sub.3 (a), J.sub.a-b = 7.68 Hz                        2.01 ppm (multiplet, 2H):                                                                          CH.sub.2 (3)                                             2.59 ppm (multiplet, 4H):                                                                          CH.sub.2 (b) and CH.sub.2 (4)                            2.88 ppm (triplet, 2H):                                                                            CH.sub.2 (2), J.sub.2-3 = 5.77 Hz                        7.25 ppm (doublet, 1H):                                                                            H.sub.5, J.sub.ortho = 8.59 Hz                           7.39 ppm (doubled doublet, 1H):                                                                    H.sub.6, J.sub.ortho = 8.59 Hz, J.sub.meta = 2.14                             Hz                                                       7.70 ppm (doublet, 1H):                                                                            H.sub.8, J.sub.meta = 2.14 Hz                            ______________________________________                                    

Mass spectrometric analysis:

    ______________________________________                                        m/e            174:        M.sup.+                                            m/e            175:        (M + 1).sup.+                                      ______________________________________                                    

STAGE D: 2-(7-ETHYL-1,2,3,4-TETRAHYDRONAPHTHYLIDEN-1 -YL)ACETONITRILE##STR40## Reactants:

7-Ethyltetralone (Stage C):0.029 mol (5 g)

Diethyl cyanomethyl phosphonate:0.048 mol (8.9 g)

Sodium hydride:0.048 mol (1.12 g)

Anhydrous tetrahydrofuran:20 cm³

Procedure:

Nitrogen gas is sparged into 20 cm³ of anhydrous tetrahydrofuran in a100 cm³ three-necked round-bottomed flask. 1.15 g of sodium hydride areadded with magnetic stirring, followed by dropwise addition of diethylcyanomethyl phosphonate.

The reaction medium is stirred for 1 h at room temperature, until theevolution of gas ceases.

The 7-ethyltetralone is added and stirring is continued for 24 h at roomtemperature, under a stream of nitrogen gas.

The reaction mixture is poured into ice.

It is extracted with 3 volumes of ether. The organic phases are washed 3times with water, dried over magnesium sulfate and then evaporated todryness.

The oil obtained is purified by column chromatography.

Characteristics:

197.27 g/mol for C₁₄ H₁₅ N

Colorless oil

Rf=0.60, eluent: acetone/toluene/cyclohexane (5/3/2)

Yield: 60%

Infrared spectroscopic analysis:

    ______________________________________                                        3050 cm.sup.-1 :    ν CH aromatic                                          2960-2820 cm.sup.-1 :                                                                             ν CH alkyl                                             2200 cm.sup.-1 :    ν CN                                                   1585 cm.sup.-1 :    ν C═C aromatic                                     ______________________________________                                    

Proton NMR spectroscopic analysis (300 MHz, DMSO-d₆, δ):

    ______________________________________                                        E Isomer:                                                                     1.22      ppm (triplet, 3H):                                                                           CH.sub.3 (a), J.sub.a-b = 8.04 Hz                    1.94      ppm (multiplet, 2H):                                                                         CH.sub.2 (3)                                         2.66      ppm (multiplet, 2H):                                                                         CH.sub.2 (2)                                         2.87      ppm (multiplet, 4H):                                                                         CH.sub.2 (b) and CH.sub.2 (4)                        5.73      ppm (singlet, 1H):                                                                           CH (c)                                               7.08      ppm (doublet, 1H):                                                                           H.sub.5, J.sub.ortho = 7.76 Hz                       7.16      ppm (multiplet, 1H):                                                                         H.sub.6, J.sub.ortho = 7.76 Hz                       7.36      ppm (multiplet, 1H):                                                                         H.sub.8                                              Z Isomer:                                                                     1.22      ppm (triplet, 3H):                                                                           CH.sub.3 (a), J.sub.a-b = 8.04 Hz                    1.94      ppm (multiplet, 2H):                                                                         CH.sub.2 (3)                                         2.66      ppm (multiplet, 2H):                                                                         CH.sub.2 (2)                                         2.87      ppm (multiplet, 4H):                                                                         CH.sub.2 (b) and CH.sub.2 (4)                        5.23      ppm (singlet, 1H):                                                                           CH (c)                                               7.08      ppm (doublet, 1H):                                                                           H.sub.5, J.sub.ortho = 7.76 Hz                       7.16      ppm (multiplet, 1H):                                                                         H.sub.6, J.sub.ortho = 7.76 Hz                       8.14      ppm (multiplet, 1H):                                                                         H.sub.8                                              ______________________________________                                    

STAGE E: (R,S) 2-(7-ETHYL-1,2,3,4-TETRAHYDRONAPHTH-1-YL)ETHYLAMINE##STR41## Reactants:

2-(7-Ethyl-1,2,3,4-tetrahydronaphthyliden-1-yl)acetnitrile

(Stage D):0.015 mol (3 g)

Absolute alcohol:150 cm³

Raney nickel:0.5g

Hydrogen:60 bar

Procedure:

3 g of 2-(7-ethyl-1,2,3,4-tetrahydronaphthyliden-1-yl)acetonitrile aredissolved in 150 cm³ of absolute alcohol in a 250 cm³ autoclave. 0.5 gof Raney nickel is added. The mixture is stirred for 6 h at 60° c. undera hydrogen pressure of 60 bar. The mixture is filtered under vacuum. Thefiltrate is evaporated to dryness. The residue is taken up in a smallvolume of ether saturated with gaseous hydrogen chloride. Theprecipitate which forms is drained and then recrystallized.

Characteristics (hydrochloride):

239.78 g/mol for C₁₄ H₂₂ CIN

White powder

Melting point:: 116°-118° C.

Rf=0.73, in acetone/toluene/cyclohexane/triethylamine (5/3/2/1)

Yield: 49%

Recrystallization solvent: ethyl acetate

Infrared spectroscopic analysis:

    ______________________________________                                        3250-2500 cm.sup.-1  ν NH.sub.3 .sup.+                                     Disappearance of the CN band                                                  1605 cm.sup.-1 :     ν C═C (aromatic)                                  ______________________________________                                    

Proton NMR spectroscopic analysis (300 MHz, DMSO d₆ δ):

    __________________________________________________________________________    1.14  ppm (triplet, 3H):                                                                     CH.sub.3 (a)    J.sub.a-b = 7.04 Hz                            1.67  ppm (multiplet, 6H):                                                                   CH.sub.2 (c), CH.sub.2 (2) and CH.sub.2 (3)                    2.63  ppm (multiplet, 7H):                                                                   CH.sub.2 (b), CH (d), CH (1) and CH.sub.2 (4)                  6.81-7.11                                                                           ppm (multiplet, 3H):                                                                   aromatic H                                                     8.00  ppm (multiplet, 3H):                                                                   NH.sub.3 .sup.+                                                __________________________________________________________________________

Elemental analysis:

Calculated: C:70.12% H:9.25% N:5.83% Cl:14.79%

Found: C:70.40% H:8.96% N:5.83% Cl:14.69%

PREPARATION 2: 2-(5-ETHYLBENZO b!THIOPHEN-3-YL)ETHYLAMINE

STAGE A: 4-ETHYLBENZENETHIOL ##STR42## Reactants:

4-Ethylbenzenesulfonyl chloride:0.024 mol (5 g)

Lithium aluminum hydride:0.096 mol (3,6 g)

Anhydrous tetrahydrofuran:20 cm³

Procedure:

3.6 g of lithium aluminum hydride are added to 20 cm³ of anhydroustetrahydrofuran with magnetic stirring in a 100 cm³ round-bottomedflask. The mixture is cooled in an ice bath and 5 g of4-ethylbenzenesulfonyl chloride are then added dropwise.

The mixture is stirred for 3 h.

The reaction mixture is poured into ice. The aqueous phase is extractedwith three volumes of ether. The organic phases are washed with water,dried over magnesium sulfate and then evaporated to dryness.

The oil obtained is chromatographed on a column.

Characteristics:

138.23 g/mol for C₈ H₁₀ S

Colorless oil

Rf=0.85 in acetone/toluene/cyclohexane (2/2/1)

Yield: 70%

Infrared spectroscopic analysis:

    ______________________________________                                        3080 cm.sup.-1 :    υ CH aromatic                                     2960-2860 cm.sup.-1 :                                                                             υ CH alkyl                                        2560 cm.sup.-1 :    υ SH                                              1490 cm.sup.-1 :    υ C═C aromatic                                ______________________________________                                    

Proton NMR spectroscopic analysis (80 MHz, DMSO-d₆ δ):

    ______________________________________                                        1.25      ppm (triplet, 3H):                                                                           CH.sub.3 (a), J.sub.a-b = 7.80 Hz                    2.65      ppm (quintet, 2H):                                                                           CH.sub.2 (b), J.sub.b-a = 7.80 Hz                    3.40      ppm (singlet, 1H):                                                                           SH (attenuated in D.sub.2 O)                         7.20      ppm (multiplet, 4H):                                                                         aromatic H                                           ______________________________________                                    

STAGE B: ETHYL 4-ETHYLPHENYLTHIOACETOACETATE ##STR43## Reactants:

4-Ethylbenzenethiol (Stage A):0.025 mol (3.2 g)

Ethyl 4-chloroacetoacetate:0.026 mol (4.2 g)

Pyridine:0.1 mol (8 cm³)

Anhydrous ether:10 cm³

Procedure:

3.2 g of 4-ethylbenzenethiol and 8 g of pyridine are dissolved in 10 cm³of anhydrous ether with magnetic stirring in a 100 cm³ round-bottomedflask. 4.2 g of ethyl 4-chloroacetoacetate are added dropwise.

The solution is stirred for 2 h at room temperature and then poured intoice.

The organic phase is extracted, washed with water, dried over magnesiumsulfate and then evaporated to dryness.

The oil obtained is purified by column chromatograpy.

Characteristics:

266.22 g/mol for C₁₄ H₁₈ O₃ S

Colorless oil

Rf=0.56 in ether/hexane/petroleum ether (2/2/1)

Yield: 50%

Infrared spectroscopic analysis:

    ______________________________________                                        2960-2860 cm.sup.-1 :                                                                             υ CH alkyl                                        Disappearance of the SH band                                                  1740 cm.sup.-1 :    υ CO ester                                        1710 cm.sup.-1 :    υ CO ketone                                       1490 cm.sup.-1 :    υ C═C aromatic                                ______________________________________                                    

Proton NMR spectroscopic analysis (80 MHz, DMSO-d₆, δ):

    ______________________________________                                        1.20      ppm (multiplet, 6H):                                                                         CH.sub.3 (a) and CH.sub.3 (f)                        2.65      ppm (quintet, 2H):                                                                           CH.sub.2 (b), J.sub.b-a = 7.90 Hz                    3.70      ppm (singlet, 2H):                                                                           CH.sub.2 (c)                                         3.75      ppm (singlet, 2H):                                                                           CH.sub.2 (d)                                         4.20      ppm (quintet, 2H):                                                                           CH.sub.2 (e), J.sub.e-f = 7.90 Hz                    7.20      ppm (multiplet, 4H):                                                                         aromatic H                                           ______________________________________                                    

STAGE C: ETHYL (5-ETHYLBENZO b!THIOPHEN-3-YL)ACETATE ##STR44##Reactants:

Ethyl 4-ethylphenylthioacetoacetate (Stage B):0.012 mol (3 g)

Polyphosphoric acid:30g

Toluene:25 cm³

Phosphorus pentoxide:0.7 g

Procedure:

25 cm³ of toluene are added to a 250 cm³ round-bottomed flask containing30 g of polyphosphoric acid, followed by addition of 0.7 g of phosphoruspentoxide. The ethyl 4-ethylphenylthioacetoacetate is then added in asingle portion and the reaction mixture is stirred for 5 h at atemperature of 50° C.

The reaction medium is poured into ice. The aqueous phase is extractedwith 3 volumes of ether. The organic phases are combined, washed with 3volumes of water, dried over magnesium sulfate and then evaporated todryness.

The oil obtained is purified by column chromatography.

Characteristics:

248.33 g/mol for C₁₄ H₁₆ O₂ S

Colorless oil

Rf=0.74, eluent: ether/hexane/petroleum ether (2/2/1)

Yield: 55%

Infrared spectroscopic analysis:

    ______________________________________                                        2950-2860 cm.sup.-1 :  υ CH alkyl                                     1730 cm.sup.-1 :       υ CO ester                                     Disappearance of the ketone CO band                                           1580 cm.sup.-1 :       υ C═C aromatic                             ______________________________________                                    

Proton NMR spectroscopic analysis (80 MHz, DMSO-d₆, δ):

    ______________________________________                                        1.20  ppm (multiplet, 6H):                                                                          CH.sub.3 (a) and CH.sub.3 (e)                           2.75  ppm (quintet, 2H):                                                                            CH.sub.2 (b), J.sub.b-a = 6.95 Hz                       3.90  ppm (singlet, 2H):                                                                            CH.sub.2 (c)                                            4.15  ppm (quintet, 2H):                                                                            CH.sub.2 (d), J.sub.d-e = 6.90 Hz                       7.20  ppm (doubled doublet 1H):                                                                     H.sub.6, J.sub.ortho =                                                        8.35 Hz, J.sub.meta = 1.40 Hz                           7.60  ppm (multiplet, 2H):                                                                          H.sub.2 and H.sub.4                                     7.90  ppm (doublet, 1H):                                                                            H.sub.7, J.sub.ortho = 8.35 Hz                          ______________________________________                                    

Elemental analysis:

Calculated: C:67.70% H:6.49% O: 12.88%

Found: C:67.64% H:6.54% O: 12.88%

STAGE D: 2-(5-ETHYLBENZO b!THIOPHEN-3-YL)ACETIC ACID ##STR45##Reactants:

Ethyl (5-ethylbenzo b!thiophen-3-yl)acetate

(Stage C):0.012 mol (3 g)

Aqueous 20% sodium hydroxide solution: 5 cm³

Methanol: 10 cm³

Procedure:

3 g of ethyl 2-(5-ethylbenzo b!thiophen-3-yl)acetate are dissolved in 10cm³ of methanol in a 50 cm³ round-bottomed flask. 5 cm³ of aqueous 20 %sodium hydroxide solution are added. The reaction mixture is stirred atroom temperature for 14 h.

It is poured into 50 cm³ of water and then extracted with 2 volumes ofether.

The aqueous phase is acidified by addition of concentrated hydrochloricacid solution (to pH 3-4).

The precipitate which forms is drained and then recrystallized.

Characteristics:

220.28 g/mol for C₁₂ H₁₂ 0₂ S

White powder

Melting point: 125°-127° C.

Rf=0.74, eluent: ether/hexane/petroleum ether (2/2/1)

Recrystallization solvent: 95° alcohol/water (1/7)

Yield: 50%

Infrared spectroscopic analysis:

    ______________________________________                                        3200-2900 cm.sup.-1 :   υ OH acid                                     2960-2840 cm.sup.-1 :   υ CH alkyl                                    1705 cm.sup.-1 :        υ CO acid                                     Disappearance of the ester CO band                                            ______________________________________                                    

Proton NMR spectroscopic analysis (300 MHz, DMSO-d₆, δ):

    ______________________________________                                        1.18      ppm (triplet, 3H):                                                                          CH.sub.3 (a)                                                                           J.sub.a-b = 7.58 Hz                          2.78      ppm (quintet, 2H):                                                                          CH.sub.2 (b)                                                                           J.sub.b-a = 7.58 Hz                          3.89      ppm (singlet, 2H):                                                                          CH.sub.2 (c)                                          7.22      ppm (multiplet, 1H):                                                                        H.sub.6                                               7.36      ppm (singlet, 1H):                                                                          H.sub.2                                               7.56      ppm (multiplet, 1H):                                                                        H.sub.4                                               7.76      ppm (multiplet, 1H):                                                                        H.sub.7  J.sub.ortho = 8.33 Hz                        9.50-10.50                                                                              ppm (massive, 1H):                                                                          COOH                                                  ______________________________________                                    

Elemental analysis:

Calculated: C:65.42% H:5.49% S:14.56% O:14.53 %

Found: C:65.32% H:5.53% S:14.65% O:14.50 %

STAGE E: (5-ETHYLBENZO b!THIOPHEN-3-YL)ACETAMIDE

Reactants:

2-(5-Ethylbenzo b!thiophen-3-yl)acetic acid

(Stage D):0.006 mol (1.4 g)

Thionyl chloride:0.024 mol (2.9 g)

Chloroform:15 cm³

Aqueous 28% ammonia solution:25 cm³ ##STR46## Procedure:

1.4 g of 2-(5-Ethylbenzo b!thiophen-3-ytmcetic acid are dissolved in 15cm³ of chloroform with magnetic stirring, in a 100 cm³ flask. 2.86 g ofthionyl chloride are added dropwise.

The solution is stirred for 3 h at room temperature and then evaporatedunder vacuum.

The residue is taken up in 30 cm³ of ether and then filtered over paper.

The filtrate is cooled in an ice bath.

25 cm³ of aqueous 28% ammonia solution are then added in a singleportion.

The precipitate is drained and then recrystallized.

Characteristics:

219.29 g/mol for C₁₂ H₁₃ NOS

White powder

Melting point: 201°-203° C.

Rf=0.35, eluent: acetone/toluene/cyclohexane (5/3/2)

Recrystallization solvent: hexane

Yield: 65%

Infrared spectroscopic analysis:

    ______________________________________                                        3340 and 3160 cm.sup.-1 :                                                                             υ NH.sub.2 amide                              2940-2840 cm.sup.-1 :   υ CH alkyl                                    Disappearance of the acid CO band                                             1650 cm.sup.-1 :        υ CO amide                                    ______________________________________                                    

Proton NMR spectroscopic analysis (80 MHz, DMSO-d₆, δ):

    ______________________________________                                        1.25   ppm (triplet, 3H):                                                                             CH.sub.3 (a)                                                                           J.sub.a-b = 7.40 Hz                          2.75   ppm (quintet, 2H):                                                                             CH.sub.2 (b)                                                                           J.sub.b-a = 7.40 Hz                          3.60   ppm (singlet, 2H):                                                                             CH.sub.2 (c)                                          7.00   ppm (multiplet, 2H):                                                                           NH.sub.2                                              7.20   ppm (doubled doublet, 1H):                                                                     H.sub.6  J.sub.ortho = 8.30 Hz                                                         J.sub.meta = 1.40 Hz                         7.50   ppm (singlet, 1H):                                                                             H.sub.2                                               7.65   ppm (doublet, 1H):                                                                             H.sub.4  J.sub.meta = 1.40 Hz                         7.85   ppm (doublet, 1H):                                                                             H.sub.7  J.sub.ortho = 8.30 Hz                        ______________________________________                                    

Elemental analysis:

Calculated: C 65.72% H:5.97% N:6.39%

Found: C 65.91% H:6.05% N:6.59%

STAGE F: (5-ETHYLBENZO b!THIOPHEN-3-YL)ACETONITRILE ##STR47## Reactants:

(5-Ethylbenzo b!thiophen-3-yl)acetamide

(Stage E):0.0011 mol (0.25 g)

Triethylamine:0.0025 mol (0.25 g)

Trifluoroacetic anhydride:0.0012 mol (0.27 g)

Anhydrous tetrahydrofuran:5 cm³

Procedure:

0.25 g of 2-(5-ethylbenzo b!thiophen-3-yl)acetamide are dissolved in 5cm³ of anhydrous tetrahydrofuran in a 50 cm³ flask, followed by additionof 0.25 g of triethylamine.

The reaction mixture is cooled in an ice-salt bath, and 0.27 g oftrifluoroacetic anhydride is added dropwise.

The solution is stirred for 1 h and then evaporated under vacuum.

The residue is taken up in water and the precipitate is drained and thenrecrystallized.

Characteristics:

201.28 g/mol for C₁₂ H₁₁ NS

White powder

Melting point: 59°-60° C.

Rf=0.82, eluent: acetone/toluene/cyclohexane (5/3/2)

Yield: 62%

Recrystallization solvent: 95° alcohol/water (4/1)

Infrared spectroscopic analysis:

    ______________________________________                                        Disappearance of the amide NH.sub.2 bands                                     2940-2830 cm.sup.-1 :   υ CH alkyl                                    2230 cm.sup.-1 :        υ CN                                          Disappearance of the amide CO band                                            ______________________________________                                    

Proton NMR spectroscopic analysis (80 MHz, DMSO-d₆, δ):

    ______________________________________                                        1.25  ppm (triplet, 3H):                                                                             CH.sub.3 (a)                                                                            J.sub.a-b = 7.50 Hz                          2.80  ppm (quintet, 2H):                                                                             CH.sub.2 (b)                                                                            J.sub.b-a = 7.50 Hz                          4.25  ppm (singlet, 2H):                                                                             CH.sub.2 (c)                                           7.30  ppm (doubled doublet, 1H):                                                                     H.sub.6   J.sub.ortho = 8.30 Hz                                                         J.sub.meta = 1.30 Hz                         7.70  ppm (multiplet, 2H):                                                                           H.sub.2 and H.sub.4                                    7.95  ppm (doublet, 1H):                                                                             H.sub.7   J.sub.ortho = 8.30 Hz                        ______________________________________                                    

Elemental analysis:

Calculated: C:71.60% H:5.51% N:6.96%

Found: C:71.78% H:5.68% N:6.99%

STAGE G: 2-(5-ETHYLBENZO b!THIOPHEN-3-YL)ETHYLAMINE ##STR48## Reactants:

(5-Ethylbenzo b!thiophen-3-yl)acetonitrile (stage F): 0.004 mol (0.7 g)

Lithium aluminum hydride: 0.01 mol (0.4 g)

Aluminum chloride: 0.01 mol (1.4 g)

Anhydrous ether: 25 cm³

Procedure:

0.4 g of lithium aluminum hydride and 1.4 g of aluminum chloride areadded with magnetic stirring to a 100 cm³ flask containing 25 cm³ ofanhydrous ether, followed by addition of 0.7 g of (5-ethylbenzob!thiophen-3-yl)acetonitrile.

After 30 min, the reaction mixture is hydrolyzed on ice and 20 cm³ ofaqueous 20% sodium hydroxide solution are added.

The ether phase is extracted, washed with 2 volumes of water, dried overmagnesium sulfate and then filtered over paper.

A stream of hydrogen chloride gas is sparged into the solution and theprecipitate formed is drained.

The hydrochloride is purified by trituration in cyclohexane.

Characteristics (hydrochloride):

241.77 g/mol for C₁₂ Hl₆ CINS

White powder

Melting point: 159°-161° C.

Rf=0.15, eluent: acetone/toluene/cyclohexane/triethylamine (5131211)

Yield: 50%

Infrared spectroscopic analysis:

    ______________________________________                                        3240-2600 cm.sup.-1     υ NH.sub.3 .sup.+                             Disappearance of the CN band                                                  ______________________________________                                    

Proton NMR spectroscopic analysis (80 MHz, CDCI₃, δ):

    ______________________________________                                        1.30 ppm (triplet, 3H):                                                                          CH.sub.3 (a)  J.sub.a-b = 7.50 Hz                          2.75 ppm (quintet, 2H):                                                                          CH.sub.2 (b)  J.sub.b-a = 7.50 Hz                          3.15 ppm (multiplet, 4H):                                                                        CH.sub.2 (c) and CH.sub.2 (d)                              7.20 ppm (multiplet, 1H):                                                                        H.sub.6       J.sub.ortho = 8.35 Hz                        7.50 ppm (multiplet, 1H):                                                                        H.sub.2                                                    7.70 ppm (multiplet, 1H):                                                                        H.sub.4                                                    7.95 ppm (doublet, 1H):                                                                          H.sub.7       J.sub.ortho = 8.35 Hz                        8.20 ppm (multiplet, 3H):                                                                        NH.sub.3 .sup.+                                            ______________________________________                                    

Elemental analysis:

Calculated: C:59.61% H:6.67% N:5.79% Cl:14.66%

Found: C:59.78% H:6.78% N:5.47% Cl:14.28%

PREPARATION 3: (R,S)2-(7-METHYL-1,2,3,4-TETRAHYDRONAPHTH-1-YL)ETHYL-AMINE

Working as in Preparation 1, but starting with toluene instead ofethylbenzene, the title compound is obtained.

PREPARATION 4: (R,S)2-(7-PROPYL-1,2,3,4-TETRAHYDRONAPHTH-1-YL)ETHYL-AMINE

Working as in Preparation 1, but replacing the ethylbenzene bypropylbenzene, the title compound is obtained.

PREPARATION 5: (R,S)2-(7-BUTYL-1,2,3,4-TETRAHYDRONAPHTH-1-YL)ETHYL-AMINE

Working as in Preparation 1, but replacing the ethylbenzene bybutylbenzene, the title compound is obtained.

PREPARATION 6: 2-(5-METHYLINDOL-3-YL)ETHYLAMINE (according to Biosci.,Biotechnol., Biochem. 1993, 57 (7), pp 1210-11) PREPARATIONS 7 TO 12:

Working as in Preparation 2, but using the appropriate reactants, thefollowing preparations are obtained:

PREPARATION 7: 2-(5-PROPYLBENZO b!THIOPHEN-3-YL)ETHYLAMINE PREPARATION8: 2-(5-BUTYLBENZO b!THIOPHEN-3-YL)ETHYLAMINE PREPARATION 9:2-(5-HEXYLBENZO b!THIOPHEN-3-YL)ETHYLAMINE PREPARATION 10:2-(5-CYCLOPROPYLBENZO b!THIOPHEN-3-YL)ETHYLAMINE PREPARATION 11:2-(5-CYCLOBUTYLBENZO b!THIOPHEN-3-YL)ETHYLAMINE PREPARATION 12:2-(5-CYCLOPROPYLMETHYLBENZO b!THIOPHEN-3-YL) ETHYLAMINE EXAMPLE 1: (R,S)N- 2-(7-ETHYL-1,2,3,4-TETRAHYDRONAPHTH-1-YL)ETHYL! ACETAMIDE ##STR49##Reactants:

(R,S) 2-(7-Ethyl-1,2,3,4-tetrahydronaphth-1-yl)ethylamine

hydrochloride: 0.008 mol (2 g)

Acetyl chloride: 0.009 mol (0.7 9)

Potassium carbonate: 0.024 mol (1.7 g)

Chloroform: 20 cm³

Water: 10 cm³

The (R,S) 2-(7-ethyl-1,2,3,4-tetrahydronaphth-1-yl)ethylaminehydrochloride from Preparation 1 is dissolved in a water/chloroformmixture (10/20) followed by addition of 3 equivalents of potassiumcarbonate. The mixture is cooled in an ice-salt bath. 1.2 equivalents ofacetyl chloride are added dropwise with vigorous magnetic stirring.Stirring is continued for 45 min.

The chloroform phase is extracted, washed with 1N hydrochloric acidsolution and then with water, dried over magnesium sulfate andevaporated to dryness.

The residue obtained is purified by chromatography.

Characteristics:

245.35 g/mol for C₁₆ H₂₃ NO

Colorless oil

Rf=0.43, eluent: acetone/toluene/cyclohexane (5/3/2)

Yield: 62%

Infrared spectroscopic analysis:

    ______________________________________                                        3260 cm.sup.-1 :    ν NH amide                                             3060 cm.sup.-1 :    ν CH aromatic                                          2980-2840 cm.sup.-1 :                                                                             ν CH alkyl                                             1630 cm.sup.-1 :    ν CO amide                                             1540 cm.sup.-1 :    ν C═C aromatic                                     ______________________________________                                    

Proton NMR spectroscopic analysis (300 MHz, DMSO-d₆, δ):

    ______________________________________                                        1.21    ppm (triplet, 3H):                                                                          CH.sub.3 (a), J.sub.a-b = 7.60 Hz                       1.80    ppm (multiplet, 6H):                                                                        CH.sub.2 (2), CH.sub.2 (3) and CH.sub.2 (c)             1.96    ppm (singlet, 3H):                                                                          CH.sub.3 (e)                                            2.58    ppm (quintet, 2H):                                                                          CH.sub.2 (b), J.sub.b-a = 7.60 Hz                       2.72    ppm (multiplet, 2H):                                                                        CH.sub.2 (4) .sub.--                                    2.81    ppm (multiplet, 1H):                                                                        CH (1)                                                  3.37    ppm (multiplet, 2H):                                                                        CH.sub.2 (d)                                            5.63    ppm (multiplet, 1H):                                                                        NH amide                                                6.96    ppm (multiplet, 3H):                                                                        aromatic H                                              ______________________________________                                    

Elemental analysis:

Calculated: C:78.32% H:9.45N:5.71%

Found: C:77.97% H:9.43% N:5.59%

EXAMPLE 2: (R,S) N- 2-(7-ETHYL-1,2,3,4-TETRAHYDRONAPHTH-1-YL)ETHYL!BUTYRAMIDE

Working in the same manner as in Example 1, but replacing the acetylchloride by butyryl chloride, the title compound is obtained. ##STR50##Reactants:

(R,S) 2-(7-Ethyl-1,2,3,4-tetrahydronaphth-1-yl)ethylamine hydrochloride:0.008 mol (2 g)

Butyryl chloride:0.009 mol (1 g)

Potassium carbonate:0.024 mol (3.3 g)

Chloroform:20 cm³

Water:10 cm³

Characteristics:

273.40 g/mol for C₁₈ H₂₇ NO

White powder

Melting point: 54°-56° C.

Yield: 75%

Purified by column chromatography in ethyl acetate

EXAMPLE 3: (R,S) N-2-(7-ETHYL-1,2,3,4-TETRAHYDRONAPHTH-1-YL)ETHYL!CYCLO-PROPANECARBOXAMIDE##STR51##

Working in the same manner as in Example 1, but replacing the acetylchloride by cyclopropanecarboxylic acid chloride, the title compound isobtained.

Reactants:

(R,S) 2-(7-Ethyl-1,2,3,4-tetrahydronaphthalene)ethylamine

hydrochloride:0.008 mol (2 g)

Cyclopropanecarboxylic acid chloride:0.009 mol (1 g)

Potassium carbonate:0.024 mol (3.3 g)

Chloroform:20 cm³

Water:10cm³

Characteristics:

271.39 g/mol for C₁₈ H₂₅ NO

White powder

Melting point: 95°-97° C.

Yield: 80%

Recrystallization solvent: hexane

EXAMPLE 4: (R,S) N- 2-(7-ETHYL-1,2,3,4-TETRAHYDRONAPHTH-1 -YL)ETHYL!TRIFLUOROACETAMIDE ##STR52## Reactants:

(R,S) 2-(7-Ethyl-1,2,3,4-tetrahydronaphth-1-yl)ethylamine

hydrochloride: 0.008 mol (2 g)

Trifluoroacetic anhydride: 0.009 mol (2 g)

Pyridine: 10 cm³

2 g of (R,S) 2-(7-ethyl-1,2,3,4-tetrahydronaphth-1-yl)ethylaminehydrochloride are dissolved in 10 cm³ of pyridine with magneticstirring, in a 50 cm³ flask.

The reaction mixture is cooled in ice.

2 9 of trifluoroacetic anhydride are added dropwise. Stirring iscontinued for 30 min. The mixture is poured into ice. The aqueous phaseis extracted with 3 volumes of ether. The organic phases are combined,washed with 3 volumes of water, dried over magnesium sulfate and thenevaporated under vacuum.

The residue obtained is purified by column chromatography thenrecristallized

Characteristics:

299.33 g/mol for C₁₆ H₂₀ F₃ NO

White powder

Melting point: 66°-69° C.

Yield: 60%

Purified by column chromatography (eluent: ethyl acetate)

Recristallisation solvant: hexan

Infrared spectroscopic analysis:

    ______________________________________                                        3280 cm.sup.-1 :    ν NH amide                                             3070 cm.sup.-1 :    ν C--H aromatic                                        2960-2840 cm.sup.-1 :                                                                             ν C--H alkyl                                           1630 cm.sup.-1 :    ν C--O amide                                           1550 cm.sup.-1 :    ν C--C aromatic                                        ______________________________________                                    

NMR spectroscopic analysis (300 MHz, CDCI₃, δ):

    ______________________________________                                        1.21  ppm (triplet, 3H):                                                                         CH.sub.3 (a)   J.sub.a-b = 7.59 Hz                         1.85  ppm (multiplet, 6H):                                                                       CH.sub.2 (c), CH.sub.2 (2) and                                                CH.sub.2 (3),                                              2.58  ppm (quintet, 2H):                                                                         CH.sub.2 (b)   J.sub.b-a = 7.59 Hz                         2.73  ppm (multiplet, 2H):                                                                       CH.sub.2 (4)                                               2.84  ppm (multiplet, 1H):                                                                       CH (1)                                                     3.74  ppm (multiplet, 2H):                                                                       CH.sub.2 (d)                                               6.52  ppm (multiplet, 1H):                                                                       NH                                                         6.97  ppm (multiplet, 3H):                                                                       aromatic H                                                 ______________________________________                                    

Elemental analysis:

Calculated: C:64.20% H:6.74% N:4.68% F: 19.04%

Found: C:64.13% H : 6.70% N:4.62% F: 18.78%

EXAMPLE 5: (R,S) N- 2-(7-ETHYL-1,2,3,4-TETRAHYDRONAPHTH-1-YL)ETHYL!VALERAMIDE ##STR53##

Working in the same manner as in Example 1, but replacing the acetylchloride by valeryl chloride, the title compound is obtained.

Reactants:

(R,S) 2-(7-Ethyl-1,2,3,4-tetrahydronaphth-1-yl)ethylamine

hydrochloride:0.008 mol (2 g)

Valeryl chloride:0.009 mol (1.1 g)

Potassium carbonate:0.024 mol (3.3 g)

Chloroform:20cm³

Water:10 cm³

Characteristics:

287.43 g/mol for C₁₈ H₂₉ NO

Colorless oil

Yield: 65%

Purified by column chromatography in ethyl acetate

Infrared spectroscopic analysis:

    ______________________________________                                        3290           cm.sup.-1 :                                                                              ν NH amide                                       2990-2820      cm.sup.-1 :                                                                              ν C--H alkyl                                     1630           cm.sup.-1 :                                                                              ν C═O amide                                  1530           cm.sup.-1 :                                                                              ν C═C aromatic                               ______________________________________                                    

NMR spectroscopic analysis (300 MHz, CDCI₃, δ):

    ______________________________________                                        0.91    ppm (triplet, 3H):                                                                          CH.sub.3 (h), J.sub.h-g = 7.29 Hz                       1.21    ppm (triplet, 3H):                                                                          CH.sub.3 (a)1 J.sub.a-b = 7.59 Hz                       1.33    ppm (multiplet, 2H):                                                                        CH.sub.2 (g)                                            1.75    ppm (multipiet, 8H):                                                                        CH.sub.2 (2), CH.sub.2 (3), CH.sub.2 (c), CH.sub.2                            (f)                                                     2.15    ppm (triplet, 2H):                                                                          CH.sub.2 (e), J.sub.e-f 7.57 Hz                         2.58    ppm (quintet, 2H):                                                                          CH.sub.2 (b), J.sub.b-a = 7.59 Hz                       2.71    ppm (multiplet, 2H):                                                                        CH.sub.2 (4)                                            2.80    ppm (multiplet, 1H):                                                                        CH (1)                                                  3.37    ppm (multiplet, 2H):                                                                        CH.sub.2 (d)                                            5.71    ppm (multiplet, 1H):                                                                        NH                                                      6.97    ppm (multiplet, 3H):                                                                        aromatic H                                              ______________________________________                                    

EXAMPLES 6 TO 12:

Working in the same manner as in Example 1, but using the appropriateacyl chloride or iso(thio)cyanate, the following examples are obtained:

EXAMPLE 6: (R,S) N- 2-(7-ETHYL-1,2,3,4-TETRAHYDRONAPHTH-1-YL)ETHYL!CYCLOBUTYLCARBOXAMIDE EXAMPLE 7: (R,S) N-2-(7-ETHYL-1,2,3,4-TETRAHYDRONAPHTH-1-YL)ETHYL!-PROPIONAMIDE EXAMPLE 8:(R,S) N- 2-(7-ETHYL-1,2,3,4-TETRAHYDRONAPHTH-1-YL)ETHYL!-ISOBUTYRAMIDEEXAMPLE 9: (R,S) N-2-(7-ETHYL-1,2,3,4-TETRAHYDRONAPHTH-1-YL)ETHYL!-N'-METHYLUREA EXAMPLE10: (R,S) N-2-(7-ETHYL-1,2,3,4-TETRAHYDRONAPHTH-1-YL)ETHYL!-N'-PROPYLUREA EXAMPLE11: (R,S) N-2-(7-ETHYL-1,2,3,4-TETRAHYDRONAPHTH-1-YL)ETHYL!-N'-CYCLOPROPYLUREAEXAMPLE 12 : (R,S) N-2-(7-ETHYL-1,2,3,4-TETRAHYDRONAPHTH-1-YL)ETHYL!-N'-CYCLOBUTYLUREAEXAMPLE 13: (R,S) N-2-(5-ETHYLBENZOTHIOPHEN-3-YL)ETHYL!CYCLOBUTANE-CARBOXAMIDE

Working in the same manner as for the amidation reaction of Example 1,but replacing the 2-(7-ethyl-1,2,3,4-tetrahydronaphth-1-yl)ethylamine by2-(5-ethylbenzo b! thiophen-3-yl)ethylamine (Preparation 2) and theacetyl chloride by cyclobutanecarboxylic acid chloride, the titlecompound is obtained. ##STR54## Reactants:

2-(5-Ethylbenzo b!thiophen-3-yl)ethylamine hydrochloride:0.001 mol (0.25g)

Potassium carbonate:0.003 mol (0.4 g)

Cyclobutanecarboxylic acid chloride:0.0013 mol (0.16 g)

Chloroform:16 cm³

Water:8 cm³

Characteristics:

286.40 g/mol for C₁₇ H₂₀ NOS

White powder

Melting point: 105°-107° C.

Rf=0.70, eluent: acetone/toluene/cyclohexane (5/3/2)

Recrystallization solvent: hexane

Yield: 70%

Infrared spectroscopic analysis:

    ______________________________________                                        3275           cm.sup.-1 :                                                                              ν NH amide                                       3070           cm.sup.-1 :                                                                              ν CH aromatic                                    2980-2840      cm.sup.-1 :                                                                              ν CH alkyl                                       1630           cm.sup.-1 :                                                                              ν CO amide                                       1550           cm.sup.-1 :                                                                              ν C═C aromatic                               ______________________________________                                    

Proton NMR spectroscopic analysis (300 MHz, DMSO-d₆, δ):

    ______________________________________                                        1.25    ppm (triplet, 3H):                                                                           CH.sub.3 (a) J.sub.a-b = 7.53 Hz                       1.97    ppm (multiplet, 6H):                                                                         CH.sub.2 (f), CH.sub.2 (f) and CH.sub.2 (g)            2.57    ppm (quintet, 2H):                                                                           CH.sub.2 (b) J.sub.b-a = 7.53 Hz                       2.95    ppm (multiplet, 3H):                                                                         CH.sub.2 (c)                                           3.36    ppm (multiplet, 2H):                                                                         CH.sub.2 (d)                                           7.25    ppm (multiplet, 1H):                                                                         H.sub.6 J.sub.ortho = 8.27 Hz                          7.40    ppm (singlet, 1H):                                                                           H.sub.2                                                7.68    ppm (multiplet, 1H):                                                                         H.sub.4                                                7.85    ppm (multiplet, 2H):                                                                         H.sub.7 and NH                                         ______________________________________                                    

Elemental analysis:

Calculated: C:71.29% H:7.04% N:4.89% Cl:11.20%

Found: C:70.88% H:7.32% N:4.90% Cl:11.02%

EXAMPLE 14: N- 2-(5-ETHYLBENZOTHIOPHEN-3-YL)ETHYL!ACETAMIDE

Working in the same manner as for the synthesis of the compound ofExample 14, but replacing the cyclobutanecarboxylic acid chloride byacetyl chloride, the title compound is obtained.

Characteristics:

247.36 g/mol for C₁₄ Hl₇ NOS

Melting point: 87°-88° C.

EXAMPLES 15 TO 24:

Starting with N- 2-(5-ethylbenzothiophen-3-yl)!ethylamine, but using theappropriate acid chloride or isocyanate, the following examples areobtained:

EXAMPLE 15: N- 2-(5-ETHYLBENZOTHIOPHEN-3-YL)ETHYL!BUTYRAMIDE

Melting point: 62°-64° C.

EXAMPLE 16: N- 2-(5-ETHYLBENZOTHIOPHEN-3-YL)ETHYL!PROPIONAMIDE

Melting point: 92°-93° C.

EXAMPLE 17: N- 2-(5-ETHYLBENZOTHIOPHEN-3-YL)ETHYL!VALERAMIDE

Melting point: 61°-630 C

EXAMPLE 18: N-2-(5-ETHYLBENZOTHIOPHEN-3-YL)ETHYL!CYCLOPROPANE-CARBOXAMIDE

Melting point: 92°-94° C.

EXAMPLE 19: N-2-(5-ETHYLBENZOTHIOPHEN-3-YL)ETHYL!CYCLOHEXANE-CARBOXAMIDE EXAMPLE 20:N- 2-(5-ETHYLBENZOTHIOPHEN-3-YL)ETHYL! N'-PROPYLUREA

Melting point: 137°-1390° C.

EXAMPLE 21: N- 2-(5-ETHYLBENZOTHIOPHEN-3-YL)ETHYL!-N'-METHYLUREA

Melting point: 133°-135° C.

EXAMPLE 22: N- 2-(5-ETHYLBENZOTHIOPHEN-3-YL)ETHYL!-N'-ETHYLUREA EXAMPLE23: N- 2-(5-ETHYLBENZOTHIOPHEN-3-YL)ETHYL!-N'-CYCLOPROPYL-UREA EXAMPLE24: N- 2-(5-ETHYLBENZOTHIOPHEN-3-YL)ETHYL!-N'-CYCLOHEXYLUREA EXAMPLE 25:N- 2-(5-ETHYLBENZOTHIOPHEN-3-YL)ETHYL!TRIFLUORO-ACETAMIDE EXAMPLE 26: N-2-(5-METHYLINDOL-3-YL)ETHYL!ACETAMIDE

Working in the same manner as for the amidation reaction of Example 1,but using 5-methyltryptamine (Preparation 6) and acetyl chloride asreactants, the title compound is obtained.

EXAMPLES 27 TO 31:

Starting with 5-methyltryptamine, but using the appropriate acylchloride or isocyanate, the following examples are obtained:

EXAMPLE 27: N- 2-(5-METHYLINDOL-3-YL)ETHYL!CYCLOPROPANECARBOXAMIDEEXAMPLE 28: N- 2-(5-METHYLINDOL-3-YL)ETHYL!BUTYRAMIDE EXAMPLE 29: N-2-(5-METHYLINDOL-3-YL)ETHYL! TRIFLUOROACETAMIDE EXAMPLE 30: N-2-(5-METHYLINDOL-3-YL)ETHYL!-N'-METHYLUREA EXAMPLE 31: N-2-(5-METHYLINDOL-3-YL)ETHYL!-N'-PROPYLUREA EXAMPLE 32: (R,S) N-2-(7-METHYL-1,2,3,4-TETRAHYDRONAPHTH-1 -YL)ETHYL!-ACETAMIDE

Working in the same manner as for the reaction for the amidation of thecompound of Example 1, but using2-(7-methyl-1,2,3,4-tetrahydronaphth-1-yl)ethylamine (Preparation 3) andacetyl chloride as reactants, the title compound is obtained.

EXAMPLES 33 TO 36:

Starting with (R,S)2-(7-methyl-1,2,3,4-tetrahydronaphth-1-yl)ethylamine, but using theappropriate acyl chloride or isocyanate, the following examples areobtained:

EXAMPLE 33: (R,S) N- 2-(7-METHYL-1,2,3,4-TETRAHYDRONAPHTH-1-YL)ETHYL!CYCLO-PROPANECARBOXAMIDE EXAMPLE 34: (R,S) N-2-(7-METHYL-1,2,3,4-TETRAHYDRONAPHTH-1-YL)ETHYL!-N'-METHYLUREA EXAMPLE35: (R,S) N-2-(7-METHYL-1,2,3,4-TETRAHYDRONAPHTH-1-YL)ETHYL!-N'-PROPYLUREA EXAMPLE36: (R,S) N- 2-(7-METHYL-1,2,3,4-TETRAHYDRONAPHTH-1-YL)ETHYL!-BUTYRAMIDEEXAMPLE 37: (R,S) N- 2-(7-PROPYL-1,2,3,4-TETRAHYDRONAPHTH-1-YL)ETHYL!-ACETAMIDE

Working in the same manner as in the reaction for the amidation of thecompound of Example 1, but using (R,S)2-(7-propyl-1,2,3,4-terahydronaphth-1-yl)ethylamine (Preparation 4) asreactant, the title compound is obtained.

EXAMPLES 38 TO 41:

Starting with (R,S)2-(7-propyl-1,2,3,4-tetrahydronaphth-1-yl)ethylamine, but using theappropriate acid chloride or isocyanate, the following examples areobtained:

EXAMPLE 38: (R,S) N- 2-(7-PROPYL-1,2,3,4-TETRAHYDRONAPHTH-1-YL)ETHYL!CYCLOPROPANECARBOXAMIDE EXAMPLE 39: (R,S) N-2-(7-PROPYL-1,2,3,4-TETRAHYDRONAPHTH-1-YL)ETHYL!-N'-METHYLUREA EXAMPLE40: (R,S) N-2-(7-PROPYL-1,2,3,4-TETRAHYDRONAPHTH-1-YL)ETHYL!-N'-PROPYLUREA EXAMPLE41: (R,S) N-2-(7-PROPYL-1,2,3,4-TETRAHYDRONAPHTH-1-YL)ETHYL!-TRIFLUOROACETAMIDEEXAMPLE 42: (R,S) N- 2-(7-BUTYL-1,2,3,4-TETRAHYDRONAPHTH-1-YL)ETHYL!-ACETAMIDE

Working in the same manner as for the reaction for the amidation of thecompound of Example 1, but using 2-(7-butylnaphth-1-yl)ethylamine(Preparation 5) as reactant, the title compound is obtained.

EXAMPLES 43 TO 46:

Starting with 2-(7-butyl-1,2,3,4-tetrahydronaphth-1-yl)ethylamine, butusing the appropriate acid chloride or isocyanate, the followingexamples are obtained:

EXAMPLE 43: (R,S) N- 2-(7-BUTYL-1,2,3,4-TETRAHYDRONAPHTH-1-YL)ETHYL!-N'-METHYLUREA EXAMPLE 44: (R,S) N-2-(7-BUTYL-1,2,3,4-TETRAHYDRONAPHTH-1-YL)ETHYL!-N'-PROPYLUREA EXAMPLE45: (R,S) N- 2-(7-BUTYL-1,2,3,4-TETRAHYDRONAPHTH-1-YL)ETHYL!CYCLOPROPANECARBOXAMIDE EXAMPLE 46: (R,S) N-2-(7-BUTYL-1,2,3,4-TETRAHYDRONAPHTH-1-YL)ETHYL!-TRIFLUOROACETAMIDEEXAMPLES 47 TO 52:

Using Preparations 1 and 2, but employing the appropriateisothiocyanates, the compounds of the following examples are obtained:

EXAMPLE 47: (R,S) N-2-(7-ETHYL-1,2,3,4-TETRAHYDRONAPHTH-1-YL)ETHYL!-N'-METHYLTHIOUREAEXAMPLE 48: (R,S) N-2-(7-ETHYL-1,2,3,4-TETRAHYDRONAPHTH-1-YL)ETHYL!-N'-ETHYLTHIOUREA EXAMPLE49: (R,S) N-2-(7-ETHYL-1,2,3,4-TETRAHYDRONAPHTH-1-YL)ETHYL!-N'-PROPYLTHIOUREAEXAMPLE 50: N- 2-(5-ETHYLBENZOTHIOPHEN-3-YL)ETHYL!-N'-METHYLTHIOUREAEXAMPLE 51: N- 2-(5-ETHYLBENZOTHIOPHEN-3-YL)ETHYL!-N'-ETHYLTHIOUREAEXAMPLE 52: N- 2-(5-ETHYLBENZOTHIOPHEN-3-YL)ETHYL!-N'-PROPYLTHIOUREAEXAMPLES 53 TO 100:

Working as described above, but starting with Preparations 7 to 12, thecompounds of the following examples are obtained:

EXAMPLE 53: N- 2-(S-PROPYLBENZOTHIOPHEN3-YL)ETHYL!ACETAMIDE EXAMPLE 54:N- 2-(5-PROPYLBENZOTHIOPHEN-3-YL)ETHYL!PROPIONAMIDE EXAMPLE 55: N-2-(5-PROPYLBENZOTHIOPHEN-3-YL)ETHYL!BUTYRAMIDE EXAMPLE 56: N-2-(5-PROPYLBENZOTHIOPHEN-3-YL)ETHYL!VALERAMIDE EXAMPLE 57: N-2-(5-PROPYLBENZOTHIOPHEN-3-YL)ETHYL!CYCLOPROPANE-CARBOXAMIDE EXAMPLE 58:N- 2-(5-PROPYLBENZOTHIOPHEN-3-YL)ETHYL!CYCLOBUTANE-CARBOXAMIDE EXAMPLE59: N- 2-(5-PROPYLBENZOTHIOPHEN-3-YL)ETHYL!-N'-METHYLUREA EXAMPLE 60: N-2-(5-PROPYLBENZOTHIOPHEN-3-YL)ETHYL!-N'-PROPYLUREA EXAMPLE 61: N-2-(5-BUTYL-BENZOTHIOPHEN-3-YL)ETHYL!ACETAMIDE EXAMPLE 62: N-2-(5-BUTYLBENZOTHIOPHEN-3-YL)ETHYL!PROPIONAMIDE EXAMPLE 63: N-2-(5-BUTYLBENZOTHIOPHEN-3-YL)ETHYL!BUTYRAMIDE EXAMPLE 64: N-2-(5-BUTYLBENZOTHIOPHEN-3-YL)ETHYL!VALERAMIDE EXAMPLE 65: N-2-(5-BUTYLBENZOTHIOPHEN-3-YL)ETHYL!CYCLOPROPANE-CARBOXAMIDE EXAMPLE 66:N- 2-(5-BUTYLBENZOTHIOPHEN-3-YL)ETHYL!CYCLOBUTANE-CARBOXAMIDE EXAMPLE67: N- 2-(5-BUTYLBENZOTHIOPHEN-3-YL)ETHYL!-N'-METHYLUREA EXAMPLE 68: N-2-(5-BUTYLBENZOTHIOPHEN-3-YL)ETHYL!-N'-PROPYLUREA EXAMPLE 69: N-2-(5-HEXYLBENZOTHIOPHEN-3-YL)ETHYL!ACETAMIDE EXAMPLE 70: N-2-(5-HEXYLBENZOTHIOPHEN-3-YL)ETHYL!PROPIONAMIDE EXAMPLE 71: N-2-(5-HEXYLBENZOTHIOPHEN-3-YL)ETHYL!BUTYRAMIDE EXAMPLE 72: N-2-(5-HEXYLBENZOTHIOPHEN-3-YL)ETHYL!VALERAMIDE EXAMPLE 73: N-2-(5-HEXYLBENZOTHIOPHEN-3-YL)ETHYL!CYCLOPROPANE-CARBOXAMIDE EXAMPLE 74:N- 2-(5-HEXYLBENZOTHIOPHEN-3-YL)ETHYL!CYCLOBUTANE-CARBOXAMIDE EXAMPLE75: N- 2-(5-HEXYLBENZOTHIOPHEN-3-YL)ETHYL!-N'-METHYLUREA EXAMPLE 76: N-2-(5-HEXYLBENZOTHIOPHEN-3-YL)ETHYL!-N'-PROPYLUREA EXAMPLE 77: N-2-(5-CYCLOPROPYLBENZOTHIOPHEN-3-YL)ETHYL!ACETAMIDE EXAMPLE 78: N-2-(5-CYCLOPROPYLBENZOTHIOPHEN-3-YL)ETHYL!PROPION-AMIDE EXAMPLE 79: N-2-(S-CYCLOPROPYLBENZOTHIOPHEN-3-YL)ETHYL!BUTYRAMIDE EXAMPLE 80: N-2-(5-CYCLOPROPYLBENZOTHIOPHEN-3-YL)ETHYL!VALERAMIDE EXAMPLE 81: N-2-(5-CYCLOPROPYLBENZOTHIOPHEN-3-YL)ETHYL!CYCLOPRO-PANECARBOXAMIDEEXAMPLE 82: N-2-(5-CYCLOPROPYLBENZOTHIOPHEN-3-YL)ETHYL!CYCLO-BUTANECARBOXAMIDE EXAMPLE83: N- 2-(5-CYCLOPROPYLBENZOTHIOPHEN-3-YL)ETHYL!-N'-METHYL-UREA EXAMPLE84: N- 2-(5-CYCLOPROPYLBENZOTHIOPHEN-3-YL)ETHYL!-N'-PROPYL-UREA EXAMPLE85: N- 2-(5-CYCLOBUTYLBENZOTHIOPHEN-3-YL)ETHYL!ACETAMIDE EXAMPLE 86: N-2-(5-CYCLOBUTYLBENZOTHIOPHEN-3-YL)ETHYL!PROPION-AMIDE EXAMPLE 87: N-2-(5-CYCLOBUTYLBENZOTHIOPHEN-3-YL)ETHYL!BUTYRAMIDE EXAMPLE 88: N-2-(5-CYCLOBUTYLBENZOTHIOPHEN-3-YL)ETHYL!VALERAMIDE EXAMPLE 89: N-2-(5-CYCLOBUTYLBENZOTHIOPHEN-3-YL)ETHYL!CYCLO-PROPANECARBOXAMIDE EXAMPLE90: N- 2-(5-CYCLOBUTYLBENZOTHIOPHEN-3-YL)ETHYL!CYCLO-BUTANECARBOXAMIDEEXAMPLE 91: N- 2-(5-CYCLOBUTYLBENZOTHIOPHEN-3-YL)ETHYL!-NI-METHYL-UREAEXAMPLE 92: N- 2-(5-CYCLOBUTYLBENZOTHIOPHEN-3-YL)ETHYL!-N'-PROPYL-UREAEXAMPLE 93: N- 2-(5-CYCLOPROPYLMETHYLBENZOTHIOPHEN-3-YL)ETHYL!-ACETAMIDEEXAMPLE 94: N-2-(5-CYCLOPROPYLMETHYLBENZOTHIOPHEN-3-YL)ETHYL!-PROPIONAMIDE EXAMPLE 95:N- 2-(5-CYCLOPROPYLMETHYLBENZOTHIOPHEN-3-YL)ETHYL!-BUTYRAMIDE EXAMPLE96: N- 2-(5-CYCLOPROPYLMETHYLBENZOTHIOPHEN-3-YL)ETHYL!-VALERAMIDEEXAMPLE 97: N-2-(5-CYCLOPROPYLMETHYLBENZOTHIOPHEN-3-YL)ETHYL!-CYCLOPROPANECARBOXAMIDEEXAMPLE 98: N-2-(5-CYCLOPROPYLMETHYLBENZOTHIOPHEN-3-YL)ETHYL!-CYCLOBUTANECARBOXAMIDEEXAMPLE 99: N-2-(5-CYCLOPROPYLMETHYLBENZOTHIOPHEN-3-YL)ETHYL!-N'-METHYLUREA EXAMPLE100: N- 2-(5-CYCLOPROPYLMETHYLBENZOTHIOPHEN-3-YL)ETHYL!-N'-PROPYLUREAEXAMPLE 101: N- 2-(7-ETHYLNAPHT-1-YL)ETHYL!ACETAMIDE EXAMPLE 102: N-2-(7-ETHYLNAPHT-1-YL)ETHYL!CYCLOPROPANECARBOXAMIDE EXAMPLE 103: N-2-(7-ETHYLNAPHT-1-YL)ETHYL!CYCLOBUTANECARBOXAMIDE EXAMPLE 104: N-2-(7-ETHYLNAPHT-1-YL)ETHYL!TRIFLUOROACETAMIDE EXAMPLE 105: N-2-(7-ETHYLNAPHT-1-YL)ETHYL!N'-METHYLUREA EXAMPLE 106: N-2-(7-ETHYLNAPHT-1-YL)ETHYL!N'-PROPYLUREA EXAMPLE 107: N-2-(7-METHYLNAPHT-1-YL)ETHYL!ACETAMIDE EXAMPLE 108: N-2-(7-PROPYLNAPHT-1-YL)ETHYL!ACETAMIDE EXAMPLE 109: N-2-(7-BUTYLNAPHT-1-YL)ETHYL!ACETAMIDE EXAMPLE 110: N-2-(7-HEXYLNAPHT-1-YL)ETHYL!ACETAMIDE PHARMACOLOGICAL STUDY EXAMPLE A:STUDY OF THE ACUTE TOXICITY

The acute toxicity was evaluated after oral administration to batches of8 mice (26 ±2 grams). The animals were observed at regular intervals onthe first day and daily for the two weeks following the treatment. TheLD₅₀, leading to the death of 50% of the animals, was evaluated.

The LD₅₀ of the test products is greater than 1000 mg kg⁻¹ for the testcompounds which indicates the low toxicity of the compounds of theinvention.

EXAMPLE B: STUDY OF THE BINDING TO THE MELATONIN RECEPTORS

B1) STUDY ON SHEEP PARS TUBERALIS CELLS

The studies of the binding of the compounds of the invention to themelatonin receptors were performed according to the standard techniques,on sheep pars tuberalis cells. The pars tuberalis of the adenohypophysisis indeed characterized in mammals, by a high density of melatoninreceptors (Journal of Neuroendocrinology vol. (1), pp 1-4 (1989)).

PROCEDURE

1) Sheep pars tuberalis membranes are prepared and used as target tissuein saturation experiments in order to determine the binding capacitiesand affinities for 2- ¹²⁵ |!- iodomelatonin.

2) The sheep pars tuberalis membranes are used as target tissue, withvarious test compounds, in competitive binding experiments relative to2- ¹²⁵ |!-melatonin.

Each experiment is performed in triplicate and a range of differentconcentrations is tested for each compound.

The results make it possible to determine, after statistical treatment,the binding affinities of the test compound.

RESULTS

It is seen that the compounds of the invention possess a powerfulaffinity for the melatonin receptors, this affinity being stronger thanthat for melatonin itself.

B2) STUDY ON CHICK (GALLUS DOMESTICUS) BRAIN CELL MEMBRANES

The animals used are 12-day old chicks (Gallus domesticus). They aresacrificed between 13.00 h and 17.00 h on the day of their arrival. Thebrains are rapidly removed and frozen at -200° C. and then stored at-80° C. The membranes are prepared according to the method described byYuan and Pang (Journal of Endocrinology 128, pages 475-482, 1991). 2-¹²⁵ |!-melatonin is incubated in the presence of the membranes in asolution buffered to pH 7.4 for 60 min at 25° C. After this period, themembrane suspension is filtered (Whatman GF/C). The radioactivityretained on the filter is determined using a Beckman®) LS 6000 liquidscintillation counter.

The products used are:

2- ¹²⁵ |!-melatonin

melatonin

common products

original molecules

In primary screening, the molecules are tested at 2 concentrations (10⁻⁷and 10⁻⁵ M). Each result is the average of n=3 independent measurements.The active molecules retained according to the results of the primaryscreening formed the subject of a quantitative determination of theirefficacy (IC₅₀). They are used at 10 different concentrations.

Thus, the IC₅₀ values found for the preferred compounds of theinvention, which correspond to the values of the affinity, show that thebinding of the tested compounds of the invention is very powerful.

EXAMPLE C: FOUR-PLATE TEST

The products of the invention are administered esophageally to batchesof ten mice. One batch receives gum syrup. 30 minutes afteradministration of the products to be studied, the animals are placed inchambers the floor of which comprises four metal plates. Each time theanimal passes from one plate to another, it receives a mild electricdischarge (0.35 mA). The number of passages is recorded for one minute.After administration, the compounds of the invention significantlyincrease the number of passages, which shows the anxiolytic activity ofthe compounds of the invention.

EXAMPLE D: COMPOUNDS OF THE INVENTION ON THE CIRCADIAN RHYTHMS OF RATLOCOMOTOR ACTIVITY

The involvement of melatonin in driving, via the alternating day/nightcycle, most of the physiological, biochemical and behavioral circadianrhythms has made it possible to establish a pharmacological model forthe search for melatoninergic ligands.

The effects of the molecules are tested on a number of parameters and inparticular on the circadian rhythms of locomotor activity, whichrepresent a reliable marker of the activity of the endogenous circadianclock.

In this study, the effects of such molecules on a particularexperimental model, namely a rat placed in temporal isolation (permanentdarkness), is evaluated.

EXPERIMENTAL PROCEDURE

On their arrival at the laboratory, one-month-old male Long Evans ratsare subjected to a lighting cycle of 12 h of light per 24 h (12:12 LD).

After 2 to 3 weeks of adaptation, they are placed in cages equipped witha wheel connected to a recording system so as to detect the phases oflocomotor activity and thus to monitor the nyctohemeral (LD) orcircadian (DD) rhythms.

As soon as the rhythms recorded show evidence of a stable drivingpattern for the 12:12 LD lighting cycle, the rats are placed inpermanent darkness (DD).

Two to three weeks later, when the free, non-driven pattern (rhythmreflecting that of the endogenous clock) is clearly established, therats receive a daily administration of the test molecule.

The observations are made by virtue of the visualization of the rhythmsof activity:

rhythms of activity driven by the lighting rhythm,

disappearance of the driving pattern for the rhythms in permanentdarkness,

rhythms driven by the daily administration of the molecule; transient orlong-lasting effect.

A software program makes it possible:

to measure the duration and intensity of the activity, the period of therhythm in the animals under free, non-driven conditions and during thetreatment,

possibly to demonstrate, by spectral analysis, the existence ofcircadian and noncircadian components (for example ultradiancomponents).

RESULTS:

It is clearly seen that the compounds of the invention make it possibleto have a powerful effect on the circadian rhythm via the melatoninergicsystem.

EXAMPLE E: ANTIARRYTHMIC ACTIVITY

PROCEDURE

(Ref: LAWSON J. W. et al. J. Pharmacol. Expert. Therap. 160: 22-31,1968)

The test substance is administered intraperitoneally to a group of 3mice 30 min before exposure to anesthesia by chloroform. The animals arethen observed for 15 min. The absence of recording of arrythmia and ofcardiac frequencies above 200 beats/min (control: 400-480 beats/min) inat least two animals indicates a significant protection.

EXAMPLE F: PLATELET ANTI-AGGREGATING ACTIVITY

PROCEDURE

(Ref.: Bertele V. et al. Science. 220: 517-519, 1983 Ibid, Eur. J.Pharmacol. 85: 331-333, 1982)

The compounds of the invention (100 μg/ml) are tested for their capacityto inhibit irreversible platelet aggregation induced by sodiumarachidonate (50 μg/ml) in plateletenriched rabbit-plasma.

An inhibition of more than 50% in the maximum aggregation indicates asignificant activity for the compounds of the invention.

This in vitro test shows that the compounds of the invention are goodcandidates for the treatment of cardiovascular diseases, in particularthrombosis.

EXAMPLE G: PROLONGATION OF THE BLEEDING TIME

PROCEDURE

(Ref.: Djana E. et al. Thrombosis Research. 15: 191-197, 1979) Butler K.D. et al. Thromb. Haemostasis. 47: 46-49, 1982)

The test compounds are administered orally (100 mg/kg) to a group of 5mice 1 h before the standardized sectioning of the end of each tail (0.5mm).

The mice are immediately suspended vertically, the tails being immersedto a depth of 2 cm in a test tube containing isotonic saline solution at37° C.

The time required for the bleeding to stop for a period of 15 seconds isthen determined.

A prolongation of more than 50% in the bleeding time relative to acontrol group of animals is considered as being significant for thecompounds of the invention.

This in vivo test confirms the advantage of the compounds of theinvention for the treatment of cardiovascular pathologies, since thecompounds of the invention prolong the bleeding time.

EXAMPLE H: TEST OF HYPOBARIC HYPOXIA

PROCEDURE

(Ref.: Gotti B., and Depoortere H., Circ. Cerebrale, Congress onCerebral Circulation, Toulouse, 105-107, 1979)

The test compounds are administered intraperitoneally (100 mg/kg) to agroup of 3 mice 30 minutes before they are placed in a chamber at ahypobaric pressure of 20 cm Hg.

The prolongation of the survival time, relative to a group of animalstreated with the vehicle, by more than 100% in the absence of adepressant effect on the central nervous system indicates acerebroprotective activity of the compounds of the invention.

EXAMPLE I: PHARMACEUTICAL COMPOSITION: TABLETS

1000 tablets containing a 5 mg dose of n-2-(5-ethylbenzothiophen-3-yl)ethyl!acetamide

n- 2-(5-ethylbenzothiophen-3-yl)ethyl!acetamide . . . 5 g

wheat starch . . . 20 g

corn starch . . . 20 g

lactose . . . 30 g

magnesium stearate . . . 2 g

silica . . . 1 g

hydroxypropyl cellulose . . . 2 g

I claim:
 1. A compound selected from those of formula (I): ##STR55## in which: R₁ represents a group chosen from alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkylalkyl, and substituted cycloalkylalkyl,A forms, with the benzene ring to which it is attached, a cyclic group chosen from tetrahydronaphthalene, dihydronaphthalene, and naphthalene, R₂ represents hydrogen or alkyl, R₃ represents:a group R₃₁ : ##STR56## with X representing sulfur or oxygen and R₄ representing a group R₄₁ chosen from alkyl, substituted alkyl, alkenyl, alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkylalkyl, and substituted cycloalkylalkyl, or a group of formula (R₃₂): ##STR57## with X' representing sulfur or oxygen and R₅ representing hydrogen or group chosen from alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkylalkyl, and substituted cycloalkylalkyl,it being understood that in the description of formula (I), and except where otherwise mentioned: the term "alkyl" denotes a linear or branched group containing 1 to 6 carbon atoms, inclusive, the terms "alkenyl" and "alkynyl" denote linear or branched groups containing 2 to 6 atoms, inclusive, the term "cycloalkyl" denotes a group of 3 to 8 carbon atoms, inclusive, the term "substituted" associated with the alkyl group means that this group is substituted with one or more substituents chosen from halogen, alkyl, hydroxyl, and alkoxy, containing 1 to 6 carbon atoms, inclusive, the term "substituted" associated with the "cycloalkyl" and "cycloalkylalkyl" group means that this group is substituted with one or more groups chosen from halogen, alkyl, and oxo,and the enantiomers and diastereoisomers thereof.
 2. A compound selected from those of claim 1, wherein,R₁ represents alkyl, R₁ represents (C₂ -C₆)alkyl, R₁ represents ethyl, R₁ represents propyl, or R₁ represents butyl, A forms, with the benzene ring to which it is attached, tetrahydronaphthalene, or A forms, with the benzene ring to which it is attached, naphthalene, or A forms, with the benzene ring to which it is attached, dihydronaphthalene, R₂ represents hydrogen, or R₂ represents alkyl, R₃ represents a group R₃₁ as defined in formula (I), or R₃ represents a group R₃₂ as defined in formula (I), R₄ represents alkyl, R₄ represents cycloalkyl, or R₄ represents alkenyl, R₅ represents hydrogen, R₅ represents alkyl, or R₅ represents cycloalkyl, X represents oxygen, or X represents sulfur, X' represents oxygen, or X' represents sulfur.
 3. A compound selected from those of claim 1, which corresponds to one of the respective formulas: ##STR58## R₁, R₂, R₃ being defined in claim
 1. 4. A compound as claimed in claim 1, which is N- 2-(7-ethyl-1,2,3,4-tetrahydronaphth-1-yl)ethyl!acetamide.
 5. A compound as claimed in claim 1, which is N- 2-(7-ethyl-1,2,3,4-tetrahydronaphth-1-yl)ethyl!butyramide.
 6. A compound as claimed in claim 1, which is N- 2-(7-ethyl-1,2,3,4-tetrahydronaphth-1-yl)ethyl!cyclopropanecarboxamide.
 7. A pharmaceutical composition useful in alleviating melatoninergic disorders comprising a compound of formula (I) as claimed in claim 1, in combination with one or more pharmaceutically acceptable excipients.
 8. A method of treating a mammal afflicted with a melatoninergic disorder comprising the step of administering to the said mammal an effective amount of a compound as claimed in claim 1 for alleviating the said condition.
 9. A method of treating a mammal afflicted with a sleep disorder comprising the step of administering to the said mammal an effective amount of a compound as claimed in claim 1 for alleviating said condition. 